1. Technical Field
This invention relates generally to the treatment of alpha-1 adrenoceptor-mediated conditions.
2. Background
Alpha adrenoceptor-, and more specifically, alpha-1 adrenoceptor-mediated conditions take a variety of forms, and are suffered by a substantial subset of the population. Adrenoceptors (or adrenergic receptors) are a class of G protein-coupled receptors that are targeted by catecholamines. They specifically bind, and are thus activated by, their endogenous ligands, adrenaline (epinephrine) and noradrenaline (norepinephrine). Alpha adrenoceptors bind norepinephrine with a higher affinity than epinephrine. Alpha-1 adrenoceptors are found in smooth muscle tissue, and mediate conditions including hypertension, congestive heart failure, cardiac hyperplasia, urethral obstruction, hyperinsulinemia, lipid disorders, ergot alkaloid poisoning, pheochromocytoma, Raynaud's disease, and male impotency. Some of the known antagonists of alpha-1 adrenoceptors include phenoxybenzamine, phentolamine, prazosin, tamsulosin, and terazosin.
Benign prostatic hyperplasia (also referred to as benign prostatic hypertrophy, or BPH) is a particularly common alpha-1 adrenoceptor-mediated condition. It describes an enlargement of the prostate gland that frequently occurs as men age. The prostate gland comprises two lobes enclosed by an outer layer of tissue, and is located in front of the rectum and just below the bladder, surrounding the urethra. Its primary function is the release of fluid during sexual climax, assisting in the conduction of sperm through the urethra, and helping to neutralize pH of the vaginal canal. (National Kidney and Urologic Diseases Information Clearinghouse (NKUDIC), NIH Publication No. 06-3012: Prostate Enlargement: Benign Prostatic Hyperplasia, at http://kidney.niddk.nih.gov/kudiseases/pubs/prostateenlargement/index.htm#gland (June 2006) (last visited Oct. 26, 2006).)
Because of its proximity and position relative to the bladder and urethra, enlargement of the prostate gland may restrict the flow of urine through the urethra. The layer of tissue surrounding the prostate limits its expansion, causing the gland to press against the urethra, tending to narrow it and clamp it shut. The bladder wall subsequently thickens and becomes irritated, and begins to contract even when it contains only small amounts of urine (thereby causing frequent urination). Eventually, the bladder weakens and loses the ability to empty completely. This may lead to symptoms of a weak or interrupted urinary stream, a feeling of inability to completely empty the bladder, a feeling of delay or hesitation at the start of urination, a need to urinate frequently, especially at night, and a feeling of urgent need to urinate. (Id. at http://kidney.niddk.nih.gov/kudiseases/pubs/prostateenlargement/index.htm#common.)
Drug treatment for BPH focuses on shrinking or preventing further growth or enlargement of the prostate without surgery. Six drugs are commonly prescribed to alleviate clinical symptoms associated with an enlarged prostate, including Finasteride (PROSCAR), dutasteride (AVODART), terazosin (HYTRIN), doxazosin (CARDURA), tamsulosin (FLOMAX), and alfuzosin (UROXATRAL). Finasteride and dutasteride function by inhibiting production of the hormone DHT (dihydrotestosterone). The Medical Therapy of Prostatic Symptoms (MTOPS) Trial, supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), recently found that administration of finasteride and doxazosin together is more effective than using either drug alone to relieve symptoms of BPH and prevent further enlargement.
Terazosin, doxazosin, tamsulosin, and alfuzosin, all belonging to the class of drugs known as alpha-blockers, function by relaxing the smooth muscle of the prostate and bladder neck, resulting in improved urine flow and reduced bladder outlet obstruction. (Id. at http://kidney.niddk.nih.gov/kudiseases/pubs/prostateenlargement/index.htm#treatment.) Prazosin (MINIPRESS), an alpha-adrenergic blocker used for treating hypertension, has also been found useful in treating BPH by blocking alpha-1 receptors, which control constriction of the prostate and ureters. (MedlinePlus Drug Information: Prazosin (Systemic) at http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202475.html (page last updated Oct. 13, 2006) (last visited Oct. 26, 2006).)